Biphenyl compounds useful as muscarinic receptor antagonists

Abstract

The invention provides compounds of formula I: wherein a, b, c, m, n, q, r, W, Z 1 , Ar 1 , Z 2 , Y, R 1 , R 2 , and R 3 are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

1. A compound of formula Ic: 
       
         
           
           
               
               
           
         
         wherein:
 a is 0 or 1; R 1  is halo; 
 b is 0 or 1; R 2  is halo; 
 m is 0 or 1; 
 
         Z 1  is selected from —C(O)N(R 4 )— and —N(R 4 )C(O)—, where R 4  is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; 
         n is 0 or 1; 
         Ar 1  represents a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur; 
         q is 0 or 1; 
         Z 2  is selected from —C(O)N(R 6 )— and —N(R 6 )C(O)—, where R 6  is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; 
         r is 0, 1 or 2; 
         Y′ is 
       
       
         
           
           
               
               
           
         
         R 12  is selected from hydrogen, (1-4C)alkyl, -(1-4C)alkyleneOH, and -(1-4C)alkyleneheteroaryl; and 
         R 13  is selected from (1-4C)alkyl, -(1-4C)alkyleneOH, -(1-4C)alkyleneheteroaryl, (3-6C)cycloalkyl, -(1-4C)alkylene(3-6C)cycloalkyl, and -(1-4C)alkyleneC(O)NR 13a R 13b , where R 13a  and R 13b  are independently hydrogen or (1-4C)alkyl; 
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
       2. The compound of  claim 1 , wherein a and b each represent 0. 
     
     
       3. The compound of  claim 1 , wherein m is 0. 
     
     
       4. The compound of  claim 1 , wherein Z 1  is —N(R 4 )C(O)—, and R 4  is selected from hydrogen and (1-4C)alkyl. 
     
     
       5. The compound of  claim 4 , wherein Z 2  is —C(O)N(R 6 )— or —N(R 6 )C(O)—, and R 6  is hydrogen. 
     
     
       6. The compound of  claim 1 , wherein Z 1  is —C(O)N(R 4 )—, and R 4  is hydrogen. 
     
     
       7. The compound of  claim 6 , wherein Z 2  is —C(O)N(R 6 )— or —N(R 6 )C(O)—, and R 6  is hydrogen. 
     
     
       8. The compound of  claim 1 , wherein n is 0. 
     
     
       9. The compound of  claim 1 , wherein Ar 1  is selected from thiophene, pyridine, and furan. 
     
     
       10. The compound of  claim 1 , wherein q is 0. 
     
     
       11. The compound of  claim 1 , wherein r is 0 or 1. 
     
     
       12. The compound of  claim 1 , wherein R 12  is hydrogen and R 13  is selected from methyl, ethyl, —CH 2 CH 2 OH, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 C(O)NH 2 , pyridin-4-ylmethyl, thiophen-2-ylmethyl, furan-2-ylmethyl and 1H-imidazol-2-ylmethyl. 
     
     
       13. The compound of  claim 1 , wherein R 12  and R 13  are 1H-imidazol-2-ylmethyl. 
     
     
       14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of  claim 1 . 
     
     
       15. A compound of formula Ic: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, prepared by the process comprising:
 (a) reacting a compound of formula II: 
 
       
       
         
           
           
               
               
           
         
         or a salt thereof, with a compound of formula III: 
       
       
         
           
           
               
               
           
         
         wherein L 1  represents a leaving group; or
 (b) coupling a compound of formula IVa: 
 
       
       
         
           
           
               
               
           
         
         with a compound of formula Va: 
       
       
         
           
           
               
               
           
         
         or (b′) coupling a compound of formula IVb: 
       
       
         
           
           
               
               
           
         
         with a compound of formula Vb: 
       
       
         
           
           
               
               
           
         
         or
 (c) coupling a compound of formula VIa: 
 
       
       
         
           
           
               
               
           
         
         with a compound of formula VIIa: 
       
       
         
           
           
               
               
           
         
         or (c′) coupling a compound of formula VIb: 
       
       
         
           
           
               
               
           
         
         with a compound of formula VIIb: 
       
       
         
           
           
               
               
           
         
         or
 (d) reacting a compound of formula VIII: 
 
       
       
         
           
           
               
               
           
         
         wherein L 2  represents a leaving group, with a compound of formula IX:
   H—Y  IX
 
 
         or
 (e) reacting a compound of formula II with a compound of formula X: 
 
       
       
         
           
           
               
               
           
         
         in the presence of a reducing agent; or
 (f) reacting a compound of formula XI: 
 
       
       
         
           
           
               
               
           
         
         with a compound of formula IX in the presence of a reducing agent; and then
 (g) removing any protecting groups that may be present to provide a compound of formula Ic; and 
 (h) optionally forming a pharmaceutically acceptable salt of the compound of formula Ic; 
 wherein: 
 a is 0 or 1; R 1  is halo; 
 b is 0 or 1; R 2  is halo; 
 m is 0 or 1; 
 Z 1  is selected from —C(O)N(R 4 )— and —N(R 4 )C(O)—, where R 4  is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; 
 n is 0 or 1; 
 Ar 1  represents a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; 
 q is 0 or 1; 
 Z 2  is selected from —C(O)N(R 6 )— and —N(R 6 )C(O)—, where R 6  is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; 
 r is 0, 1 or 2; 
 Y′ is 
 
       
       
         
           
           
               
               
           
         
         
           R 12  is selected from hydrogen, (1-4C)alkyl, -(1-4C)alkyleneOH, and -(1-4C)alkyleneheteroaryl; and 
           R 13  is selected from (1-4C)alkyl, -(1-4C)alkyleneOH, -(1-4C)alkyleneheteroaryl, (3-6C)cycloalkyl, -(1-4C)alkylene(3-6C)cycloalkyl, and -(1-4C)alkyleneC(O)NR 13a R 13b , where R 13a  and R 13b  are independently hydrogen or (1-4C)alkyl.